1. Field of the Invention
The present invention relates to a method of inhibiting secretion of inflammatory cytokines in a host, and also to a method of treating diseases which involve abnormal production or abnormal secretion of inflammatory cytokines.
2. Description of the Related Art
A variety of inflammatory cytokines have been reported to be abnormally produced in many inflammatory diseases. As their participation in the mechanism of causing symptoms or pathology of the inflammatory diseases has gradually been clarified, clinical application of cytokines is now hoped for by controlling their production or developing antagonists thereto.
Differentiation of cells, in which B cells activated as a result of stimulation by antigens are proliferated into antibody-forming cells, requires the presence of certain cytokines. Among cytokines, interleukin-4 and interleukin-5 which correspond to BCGF (B cell growth factor) I and II are known to participate in proliferation of cells. Interleukin-6 (hereinafter referred to as IL-6) which is a B cell differentiation factor (BCDF) is a cytokine known to participate in differentiation.
IL-6 was first found in a supernatant of a peripheral blood monocyte culture as a factor which induces immunoglobulin production in strains of B cells transformed with EB viruses. Thereafter, they were separately investigated as independent factors such as B cell stimulatory factor-2 (BSF-2), interferon-.beta.2 (IFN-.beta.2), 26 kDa protein, hepatocyte stimulatory factor, and hybridoma plasmacytoma growth factor (HPGF) until cloning carried out by Hirano et al. in 1986 revealed that all of them are identical cytokines [Hirano, T. et al., Nature, 324, 73 (1986)].
It has been clarified that IL-6, which has important functions in the antibody-forming system of B cells in the immune system, also serves as an important factor in the protective system of living bodies such as the hematopoietic system, the nervous system, and liver, by inducing proliferation and differentiation of T cells, acting on liver cells to stimulate synthesis of acute proteins, or by stimulating the hematopoietic cells to form pluripotent colonies.
Present knowledge and reports on IL-6 or the relationship between abnormal formation or secretion of IL-6 and various diseases are as follows.
In autoimmune diseases such as hypergamma-globulinemia, rheumatoid arthritis (RA) which shows positive results against various autoantibodies, and systemic lupus erythematosus (SLE), activation of polyclonal B cells is induced. In a synovial fluid of RA patients, a great amount of IL-6, which is formed by activated T cells or B cells infiltrated into the synovial membrane tissue, is present [Hirano, T. et al., Eur. J. Immunol., 18, 1797 (1988)].
It is reported that in patients suffering from atrial myxoma and presenting symptoms of autoimmune diseases, the clinical symptoms disappear after tumors are removed. This suggests that some factor produced by tumor cells induces the symptoms. It has also been shown that tumor cells produce a great deal of IL-6, suggesting a connection between abnormal formation of IL-6 and a disease with abnormality in polyclonal B cells [Hirano, T. et al., Proc. Natl. Acad. Sci., USA, 82, 5490 (1985)].
IL-6 had already been reported to be a growth factor of mouse plasma cytoma. Recently, based on the fact that proliferation of myeloma cells obtained from human multiple myelomatosis patients is suppressed by anti-IL-6 antibodies, it has now been considered that IL-6 has the possibility of being an autoproliferation factor of myeloma cells. This suggests that IL-6 greatly participates not only in polyclonal B cell abnormalities but also in monoclonal B cell abnormalities such as myeloma [Kawano, M., et al., Nature, 332, 83 (1988)].
In Castleman syndrome accompanied by noncausal lymph node enlargement, high blood IL-6 activity is observed as well as hypergamma-globulinemia and high levels of acute proteins. When swollen lymph nodes are removed from the patients, blood IL-6 activity returns to a normal serum level, and the patients' clinical conditions are ameliorated [Yoshizaki, K. et al., Blood, 74, 1360 (1989)].
In urine samples from patients with primary glomerulonephritis, significant IL-6 activities are observed compared to samples of healthy subjects or patients with minimal change nephrotic syndrome. In tissue samples of kidney biopsy, the degree of proliferation of mesangium cells and urinary IL-6 activity are correlated. In fact, when IL-6 is added to an in vivo culture system of rat renal mesangium cells, proliferation of the cells is stimulated in a concentration dependent manner. This proves that IL-6 is a proliferative factor of mesangium cells [Horii, Y. et al., J. Immunol. 143, 3949 (1989)].
Interleukin-8 (IL-8) is a potent chemotactic and activating cytokine for neutrophilic leukocytes. It is considered to participate in various inflammatory diseases, and its clinical application is expected to be developed by controlling their formation or developing antagonists thereto. A number of reports have already been published which deal with abnormal formation of IL-8 and inflammatory diseases associated therewith. Presently, research of clinical application using anti-IL-8 antibodies is conducted [Clinical Immunology, 27 (Suppl. 16), 80-85 (1995), among others].
A monocyte chemotactic and activating factor (MCAF) which is sometimes called MCP-1 (monocyte chemoattractant protein-1) has a structure and functions similar to those of the above-mentioned IL-8. In this regard, MCAF and IL-8 constitute a family. MCAF has monocyte-specific migrating activities and exhibits eosinocyte histamine releasing actions, and therefore, it is considered to be greatly involved in inflammation and bioprotective mechanisms. Especially, its chemotactic and activating features on monocytes suggest that MCAF has some relation to inflammatory diseases, autoimmune diseases, arteriosclerosis, and tumors. On the other hand, its basophil activating feature suggests some relation to allergy reactions. In fact, it has now been clarified that overproduction of MCAF actually occurs to cause infiltration and activation of macrophages, resulting in a contribution in the formation of pathological conditions [Clinical Immunology, 27 (Suppl. 16), 155-161 (1995), among others].
A granolocyte-macrophage colony-stimulating factor (GM-CSF) has a variety of bioactivities not to speak of its outstanding role in the granulocyte/macrophage hematopoietic system. For example, like the above-mentioned cytokines, it is known to stimulate the functions of matured blood cells such as neutrophilic leukocytes, eosinocytes, and basophils. Abnormal formation of GM-CSF has been reported, for example, in RA patients, suggesting participation in the mechanism of the onset of arthritis. Moreover, from the fact that GM-CSF stimulates proliferation of white blood cells, the possibility of the presence of an autocrine growth mechanism is suggested to explain the infinite proliferation of the cells [Clinical Immunology, 27 (Suppl. 16), 202-211 (1995), among others].
Likewise, a granulocyte colony-stimulating factor (G-CSF] is known to stimulate the functions of mature neutrophilic leukocytes. It also stimulates proliferation of myeloid leukemia cells and part of solid cancerous cells [Clinical Immunology, 27 (Suppl. 16), 212-219 (1995), among others].
As mentioned above, a great many diseases are ascribed to abnormal formation or abnormal secretion of inflammatory cytokines. It is therefore considered that if secretion of inflammatory cytokines in a host typified by a human is successfully inhibited, it will be of help to the treatment of the host suffering from those diseases.
In view of the foregoing, the present inventors conducted research over various chemicals in search of substances which inhibit secretion of inflammatory cytokines, during which they unexpectedly found that digitalis compounds inhibit secretion of the inflammatory cytokines, leading to completion of the invention.